Hyaluronan (HA) is a major component of tissue extracellular matrix (ECM) and has classically been considered as a space occupying glycosaminoglycan whose primary function is to provide structural support to tissues. More recently, HA has been found to also serve as a trigger of innate immune activation once it is released from the ECM. This critical step in inflammation is dependent on HA catabolism and on recognition by receptors previously thought to be responsible only for detection of microbial invasion, such as Toll-like receptors (TLRs), as well as classical HA binding molecules such as CD44. Due to the interaction with the TLR pathway, HA also modifies the response to pathogen-associated molecules such as lipopolysaccaride, and can protect the host from an excessive septic response. Thus, HA serves a critical function in inflammation, acting to enhance cell recruitment required for wound repair but also to regulate the response of cells to microbial pathogens. Despite abundant evidence for an essential role of HA catabolism in controlling inflammation, current in vivo models of wound repair and inflammation are limited by many confounding variables. In this project we seek to better understand the function of HA in inflammation by generating novel transgenic mouse models with targeted conditional overexpression of Hyall, Hyal2 or Hyal3. Preliminary findings support our overall hypothesis that HA is an important intermediate in inflammation, and has demonstrated the feasibility of our overall approach for using expression of hyaluronidases to understand how HA functions in the complex system of innate immunity. Our aims include construction and characterization of the consequences of conditional expression of these hyaluronidases, followed by analysis of the effects of altered HA catabolism in models of inflammation and infection. Our proposal therefore expects to advance understanding of the function of HA by investigating mouse genetic models of HA catabolism and HA recognition. RELEVANCE (See instructions): The inflammatory response to injury and is a critical component of many human disorders. We have discovered that a major component of many tissues, hyaluronan, acts as a signal that injury has occurred. This project seeks to model and understand the physiological relevance of this process in mice so that we may apply this information to improve treatments of human diseases involving vascular inflammation and ti.;.;iie renair